PharmacoNutrition Reviewed

Source: JAMA (2007), 297: 842-857
Article Type: Review (Meta Analysis)
Authors: G Bjelakovic, D Nikolova, LL Gluud, R Simonetti, C Gluud

Image taken from: http://carbs.com/dimages/headlines/vitamins.jpg

The Meta-Analysis published by Bjelakovic et al. addresses an issue that is getting more and more controversial, recently, i.e. whether antioxidant supplements are actually health-beneficial, show no effect or are even detrimental. Based on the analysis of 69 randomized trials with more than 200.000 participants, the authors conclude that
a) vitamin C and selenium have no effect on mortality
b) beta-carotene, vitamin A and vitamin E (singly or combined) significantly increase mortality

What do these results tell us?
First of all, I am curious to read the comments this article will certainly provoke. The widely cited Miller et al. study on vitamin E and mortality, for example, caused a quite heated debate, especially regarding the statistics used.
Secondly, we (at least most of us) are not only consuming nutrients – but food; although I haven’t fully digested this meta-analysis, yet, the results are – if valid – not that surprising, because when antioxidants are taken in as part of real food they actually exert quite different effects I contrast to supplements. Also, the argument that the antioxidant supplements might reduce “beneficial ROS” is a bit sketchy.
I just wonder, how the food supplement industry is going to react to this study – I think it cannot get a lot more worse for them.

Source: Biogerontology (200), 7: 307-314
Article Type: Review
Authors: V Frazzini, E Rockabrand, E Mocchegiani, SL Sensi

Image Taken From:
http://upload.wikimedia.org/wikipedia/commons/thumb/7/79/
Zinc_finger_DNA_complex.png/300px-Zinc_finger_DNA_complex.png

Zinc (Zn) is the second most abundant trace element in the body (total amount approx. 2 g) and essential for human survival. Zics’s role in human physiology include a) catalytic (about 300 enzymes are Zn-dependent), b) structural (‘Zn-finger motifs in proteins) and c) regulatory (metallothioneins, immunes response, insulin metabolism) function.
Currently, a daily Zn intake of 10 mg is considered adequate. Dietary surveys showed widespread, worldwide prevalence of inadequate Zn intakes with, however, considerably lower risk in North America and Europe than other parts of the world.
Well-known clinical Zn-deficiency symptoms include a) skin lesions & delayed wound healing, b) immune deficiency, c) impaired taste and appetite and d) eye lesions. Consequently, Zn is nowadays commonly found in dietary/food supplements.

As with any nutrient, too much is too much. This brings us to the recent article by Frazzini et al. who asked the question whether Zn could actually be a link between oxidative stress and brain aging.
What caught my interest are the in nerve cells observed regional differences of Zn dysregulation, which have been suggested to trigger ‘normal’ brain aging and especially neurodegeneration.
The figure below summarizes the key aspects of the mechanisms possibly explaining Zn’s potential to induce brain cell death.

Does this now mean we should be aware of our daily Zn intake to protect our brain?
Most probably not. Although Zn toxicity (here especially peripheral symptoms) has been described in individuals repeatedly consuming more than 50 mg per day, the blood brain barrier, which regulates Zn homeostasis of the brain, is comparatively impermeable to changes in the concentration of blood metal ions. This does, of course, not mean that one cannot deplete the brain of Zn when significantly cutting down oral Zn intake.
In terms of neurodegeneration, for example Alzheimer’s disease, current believe is that the toxic effects of Zn are due to disruption of the brain endogenous Zn homeostasis, a hypothesis which is supported by studies in neuronal-specific Zn-transporter knockout mice.

As a general comment, I think Zn deficiency is a far bigger problem that chronic Zn overload for the majority of people. So, despite the increasing number of studies linking brain Zn with neurodegeneration, the above mentioned facts hopefully made clear that there’s only little - better to say no - hope of preventing neurodegeneration by reducing Zn intake. Vice versa, increase Zn intake above the current RDA to boost the body’s antioxidant and subsequently disease resistance, as suggested in various publications, must also be discouraged due to lack of evidence.

FIGURE: Mechanism of Zn-mediated Neurodegeneration

Source: Trends in Neuroscience (2006), 29: 632-639
Article Type: Review
Authors: MP Mattson, A Cheng

Image taken from: http://www.bad-bad.de/gesch/paracel.gif

Recently, the hormesis theory is gaining momentum for explaining the health-beneficial effects of diets rich in fruits and vegetables. Actually, one of the first to describe hormetic effects of any substance applied to living things has been Paracelsus, one of the most famous scientists of the 16th century.
What is hormesis? The term describes the induction of health-beneficial effects due to the low-dose presence of agents that are toxic at higher concentrations (adaptive response). In this regard, phytochemicals (such as polpyhenols) can be considered as mild stressors provoking the up-regulation of the endogenous antioxidant network. This in turn would enable an organism to better cope with an increasing production of reactive oxidative and nitrosative species (ROS and RNS), for example in disease states. Consequently, the detrimental degeneration of proteins, fatty acids, sugars and DNA would be avoided. In the long run, this could finally lead to a healthier aging process, characterised by a lower burden of chronic, lifestyle maladies. Mattson and Cheng support this concept by summarising recent data obtained with, amongst others, the neurohormetic phytochemicals resveratrol and curcumin in vitro and in vivo.

Personally, I feel quite comfortable with this theory. However, whether it will help to answer the recurring question of whether an increase/decrease in biomarkers such as antioxidant capacity or antioxidant enzyme activity upon incubation/intake of phytochemicals is actually beneficial or detrimental, only time will tell.

For further reading, I recommend: Arumugam et al., 2006 and Hipkiss, 2006 and Hayes, 2007.

After a short trip overseas, I am now back in the office and will resume keeping you up-dated on recent trends in pharmaconutrition. Sorry for the time-out! Baste

Image taken from: http://static.twoday.net/spiegelei/images/Bildstoerung.jpg

Source: Aging Cell (2007), 6: 15-25
Article Type: Original Contribution
Authors: TG Valencak, T Ruf

Image taken from:
http://www.macvillage.de/blog/wp-content/uploads/2006/07/dali_zeit.jpg

Omega-3 fatty acids (n-3) are generally considered as health-beneficial (see also post discussed yesterday). When talking about the lifespan of mammals, however, n-3 fatty acids seem to hamper longevity. The reason for this correlation has been linked to:
• the high susceptibility of polyunsaturated fatty acids (PUFA; n-3, n-6) to oxidation
• the boost in basal metabolic rate (BMC) in the presence of PUFA, e.g. by up-regulating the activity of membrane-associated proteins
These effects have been summarized in the ‘membrane pacemaker theory of aging’: PUFA (up) –> BMR (up) –> longevity (down).

After correcting for body weight and phylogenetic effects, Valencak & Ruf found a clear correlation between the ratio of n3:n6 in muscle and maximum lifespan (MLS), based on the analysis of 42 mammalian species. Noteworthy, MLS was unrelated to docosahexaenoic (DHA, n-3) content, total membrane unsaturation as well as BMR, thus questioning the ‘membrane pacemaker theory of aging’.
Does this mean now that we should avoid consuming PUFAs, particularly n-3?
I would say no, because the current recommendation (see also Simopoulos, 2006) to increase dietary n-3 intake is largely based on the discrepancy in the composition of ingested dietary fat between western societies (n-3:n-6 = 1:15) and our hunting & gathering ancestors (n-3:n-6 = 1:1). Hence, the risk of reducing your (maximum) lifespan by consuming n-3-rich plant and animal foods (which consequently will enhance your n-3:n-6 ratio) is rather small.

Source: Critical Care Medicine (2007), 35: 544-554
Article Type: Original Contribution
Authors: MB Schaefer, J Ott, A Mohr, MH B, A Grosz, N Weissmann, S Ishii, F Grimminger, W Seeger K Mayer

Image taken from: http://doreen.mkbmemorial.com/NF/photos/ICU.JPG

Most intensive care patients are sooner or later affected by the systemic inflammatory response syndrome (SIRS). Hallmark of SIRS is the elevated production of certain eicosanoids possessing strong pro-inflammatory properties. Eicosanoids are derived from its precursor arachidonic acid, an omega-6 (n-6) fatty acid commonly found in biological membranes.
Arachidonic acid (20:4, n-6) in turn can be synthesizes from linoleic acid (18:2, n-6), the main fatty acid found in soy oil-based lipid emulsions, such as Lipoven (Fresenius Kabi, Germany). In contrast, cold water fish are rich in omega-3 fatty acids (especially eicosapentaenoic and docosahexaenoic acid), which are generally considered to show anti-inflammatory activity.
In their recent article, Schaefer et al. compare in a model of murine acute lung injury the inflammatory effect of Lipoven with that of the n-3-rich lipid formulation Omegaven (Fresenius Kabi, Germany). In agreement with previous reports, Lipoven promotes the production of pro-inflammatory biomarkers whereas the application of Omegaven leads to opposite effects. Here it is important to note that the impact of both formulations depends on the experimental design, i.e. the permanent infusion of the mice with the lipid emulsions. The authors point out that it is questionable whether the same effects could be provoked by oral intake of either lipid formulation.
Mechanistically, the article provides an interesting insight in the regulation of inflammation. Platelet-activating factor (PAF)-receptor knock-out mice (-/-) showed an inflammatory response comparable to those of wild type mice. However, neither Lipoven nor Omegaven were able to module the production of inflammatory biomarkers in PAF -/-, suggesting that both PAF and PAF-receptor are important for communicating the molecular signals exerted by n-3- and n-6.
In a nutshell, the administration of lipid emulsions might not only be means to supply the critically ill with enough energy, but also help to modulate the immune system towards pro- or anti-inflammatory response.

Another interesting report on the effect of n-3 in ICU patients can be found on the webpage of the Children’s Hospital Boston.

In the February 01, 2007 edition of Sciencexpress, Libert et al. report on the regulation of Drosophila life span by olfaction and food-derived odors.

Image taken from:
http://athens.uchicago.edu/~lenka/images/drosophila-head.jpg

Caloric (dietary) restriction has been shown to modulate the lifespan of many different species, such as Drosophila m., C. elegans or rodents.
I find the fact that exposure to nutrient-derived odorants itself modulates lifespan quite intriguing and recommend for further reading the following two links: Science and The Scientist

Source: Journal of Neurochemistry (2007), 100: 736-746
Article Type: Original Contribution
Authors: F. Herrera, V. Martin, G. Garcia-Santos, J. Rodriguez-Blanco, I. Antolin, C. Rodriguez

Image taken from:
http://www.virginia.edu/insideuva/2005/11/images/Jet_Lag_Graphic.jpg

Life depends on information. Melatonin, which occurs ubiquitiously in plants and animals, has been suggested as one of the first signals appearing on earth. In vertebrates, it is mainly synthesized in the pineal gland (but also other tissues) from the neurotransmitter serotonin. Melatonin, due to its chronobiotic activity, effectively attenuates jet lag symptoms, especially with eastbound flights. Moreover, melatonin has been shown to prevent neuronal cell death both in vitro and in vivo.
The article by Herrera et al. provides further inside in the mechanism of melatonin-mediated neuroprotection. The authors suggest for melatonin a novel, direct antioxidant effect targeted to the mitochondria, the key source of potentially deleterious reactive oxygen species (ROS) in cells. The protective effects of melatonin in murine hippocampal cells, however, where detected with a melatonin concentration of 1 mM (= 1000 µM), which is in contrast not only to the low micromolar concentrations that have been reported as physiological concentrations of melatonin but also to pharmacological levels, which range between 100 nM-10 µM (Kolar et al.). Bearing in mind these facts, it is somewhat difficult to estimate whether melatonin exerts the aforementioned mode of action in vivo, too.

Source: European Journal of Clinical Nutrition (2007), 61: 69-76
Article Type: Original Contribution
Authors: S Valtuena, D del Rio, N Pellegrini, D Ardigo, L Franzini, S Salvatore, PM Piatti, P Riso, I Zavaroni, F Brighenti

Image taken from: http://www.healingwithnutrition.com/graphic/vitamins.gif

In my last post I pointed out the lack of disease-preventing efficiency antioxidants (e.g. polpyhenols, vtaminc C and E, carotenoids) show in many intervention studies.
In their recent paper, Valtuena et al. suggest that the total antioxidant capacity (TAC) of the diet acts as an independent predictor of plasma beta-carotene (a carotenoid) levels. They derive this conclusion from covariate analyses of their data showing a significant correlation between TAC of the diet and plasma beta-catotene levels. In contrast, the impact of oral beta-carotene intake on plasma levels was only of marginal significance, suggesting that plasma concentrations of beta-carotene are modulated by other determinants than its own intake. In summary, they conclude that a high TAC of the diet leads to enhanced plasma beta-carotene levels, possibly by preventing beta-carotene breakdown due to absorption of other antioxidants present in the diet. This in turn might also explain why high intake of fruits and vegetables not only lead to higher beta-carotene plasma concentrations but is also health beneficial, whereas supplementation with beta-carotene fails to reduce disease risk.

Aside from the TAC of the diet or food items, plasma or serum TAC is another parameter frequently reported in research papers.
The question now is whether the TAC of the diet (determined by the presence of antioxidants in the food) is linked to TAC of the plasma.
Here, I would like to draw your attention to a research article published in 2004 (Lotito et al.) showing that the consumption of apples (which are considered as antioxidant-rich food) indeed inceases plasma TAC. However, the changes in plasma TAC were due to effects of fructose (which is present in high amounts in apples, too) on plasma ureate (a major endogenous plasma antioxidant) levels (and not due to effects of ascorbate, i.e. vitamin C, present in the apples)
Taken together, those studying dietary effects on plasma TAC must rule out postprandial (and other confounding) effects on plasma TAC, prior directly linking the antioxidants present in the food under investigation to observed changes in plasma TAC.